Tuberculosis (TB) remains the leading infectious cause of mortality in the world today. Both treatment and control of this deadly disease are increasingly hampered by the emergence of multidrug resistant (MDR) strains of M. tuberculosis. While poor compliance and/or inadequate TB therapy clearly provides the selection pressure driving the evolution of drug resistant strains, the process is complex, likely involving both host and mycobacterial determinants as well. We hypothesize that interactions between selected mycobacterial properties that interfere with the induction of the host immune response or resist the effects of this response can act to increase bacillary growth and survival and thus the propensity of acquiring drug resistance. The consequence of this occurring over time will be an enrichment of specific strains among the drug resistant cases within communities where TB is endemic. Our overall goal in these studies is to define determinants in M. tuberculosis that can contribute to develop drug resistance in human populations. We propose to 1) Carry out a carefully designed case-control study to characterize the natural distribution of MDR-TB and non-MDR-TB M. tuberculosis strains circulating in a defined human population with high endemic TB;2) Test the hypothesis that an M. tuberculosis phenol glycolipid (PGL-tb), which induces a host immune response that fails to control bacillary growth efficiently, is therefore associated with an increased resistance in the host;and 3) Examine the interaction between host oxidative stress and DNA repair mechanisms in the acquisition of drug resistance in M. tuberculosis. Because a multidisciplinary approach is required to achieve these objectives, we have assembled a team of collaborators with a range of expertise to enable us to tease apart the many facets of this complex infectious disease problem. Multidrug-resistant tuberculosis (MDR TB) is associated with high morbidity and mortality, prolonged treatment to cure, and increased risk of spread in the community. We will test the hypothesis that some naturally occurring strains of M. tuberculosis are more prone to develop drug resistance than others. Results of these studies can contribute to improved TB control strategies aimed at reducing the emergence of MDR- TB and the development of new therapeutic approaches for combating this deadly disease.